High Cortisol response to adrenocorticotropin (ACTH) is associated with an increased propensity to obesity through reduced melanocortin signalling (#159)

In
humans, higher cortisol responses to stress coincides with increased food
intake1 .
We have identified sub-populations of ewes that have either high (HR) or low
(LR) cortisol responses to ACTH (10% from each extreme). When placed on a high
energy diet, HR have a greater increase in adiposity than LR, which is not due
to different food intake but is associated with reduced post-prandial
thermogenesis in skeletal muscle2 .
Hypothalamic appetite-regulating peptides (ARP) exert reciprocal effects on
food intake and energy expenditure/thermogenesis. The main aim of this study was to characterise differences in
expression and function of ARP in HR and LR ewes. In situ hybridization (n=4/group) was used to quantify the expression
of genes for neuropeptide Y (NPY) proopiomelanocortin (POMC), melanocortin
receptors (MC3R & MC4R), orexin and melanin-concentrating hormone (MCH). Expression
of NPY and POMC was similar in LR and HR, but LR had higher levels of expression
of MCH (P<0.05), orexin (P<0.01) MC3R (P<0.05) and MC4R (P<0.001).
Intracerebroventricular (icv) infusions (N=6/group, 1000-1600h) of NPY (50µg/h), α-melanocyte
stimulating hormone (αMSH),
orexin and MCH were performed in ewes entrained to a daily meal feeding (food
available between 1100-1600h). Post-prandial thermogenesis in muscle was higher
(P<0.05) in LR. The temperature response to MCH infusion was lower in LR
than in HR, with no effect of NPY, αMSH
or orexin infusion. NPY, MCH and orexin did not stimulate food intake in
meal-fed animals and αMSH
reduced food intake (P<0.01) in LR only. With 24h infusions, NPY increased
(P<0.001) food intake in both groups but αMSH
was only effective in LR (P<0.05). We conclude that HR are resistant to the
satiety effects of αMSH
and this is most likely due to reduced expression of MC3R and MC4R. Thus, the
higher propensity of HR to become obese is associated with reduced melanocortin
signalling.